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Original article
Randomised controlled trial of GM-CSF in critically ill patients with impaired neutrophil phagocytosis
  1. Emma M Pinder1,
  2. Anthony J Rostron1,
  3. Thomas P Hellyer1,
  4. Marie-Helene Ruchaud-Sparagano1,
  5. Jonathan Scott1,
  6. James G Macfarlane1,
  7. Sarah Wiscombe1,
  8. John D Widdrington1,
  9. Alistair I Roy2,
  10. Vanessa C Linnett3,
  11. Simon V Baudouin4,
  12. Stephen E Wright5,
  13. Thomas Chadwick6,
  14. Tony Fouweather6,
  15. Jatinder K Juss7,
  16. Edwin R Chilvers7,
  17. Susan A Bowett8,
  18. Jennie Parker8,
  19. Daniel F McAuley9,
  20. Andrew Conway Morris10,
  21. A John Simpson1
  1. 1 Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, UK
  2. 2 Integrated Critical Care Unit, Sunderland Royal Hospital, Sunderland, UK
  3. 3 Intensive Care Unit, Queen Elizabeth Hospital, Gateshead, UK
  4. 4 Intensive Care Unit, Royal Victoria Infirmary, Newcastle upon Tyne, UK
  5. 5 Intensive Care Unit, Freeman Hospital, Newcastle upon Tyne, UK
  6. 6 Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK
  7. 7 Department of Medicine, University of Cambridge, Cambridge, UK
  8. 8 Newcastle Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK
  9. 9 Centre for Experimental Medicine, Queen’s University Belfast, Belfast, UK
  10. 10 Division of Anaesthesia, University of Cambridge, Cambridge, UK
  1. Correspondence to Professor A John Simpson, Institute of Cellular Medicine, Medical School, Newcastle University, Newcastle upon Tyne NE2 4HH, UK; j.simpson{at}ncl.ac.uk

Abstract

Background Critically ill patients with impaired neutrophil phagocytosis have significantly increased risk of nosocomial infection. Granulocyte-macrophage colony-stimulating factor (GM-CSF) improves phagocytosis by neutrophils ex vivo. This study tested the hypothesis that GM-CSF improves neutrophil phagocytosis in critically ill patients in whom phagocytosis is known to be impaired.

Methods This was a multicentre, phase IIa randomised, placebo-controlled clinical trial. Using a personalised medicine approach, only critically ill patients with impaired neutrophil phagocytosis were included. Patients were randomised 1:1 to subcutaneous GM-CSF (3 μg/kg/day) or placebo, once daily for 4 days. The primary outcome measure was neutrophil phagocytosis 2 days after initiation of GM-CSF. Secondary outcomes included neutrophil phagocytosis over time, neutrophil functions other than phagocytosis, monocyte HLA-DR expression and safety.

Results Thirty-eight patients were recruited from five intensive care units (17 randomised to GM-CSF). Mean neutrophil phagocytosis at day 2 was 57.2% (SD 13.2%) in the GM-CSF group and 49.8% (13.4%) in the placebo group, p=0.73. The proportion of patients with neutrophil phagocytosis≥50% at day 2, and monocyte HLA-DR, appeared significantly higher in the GM-CSF group. Neutrophil functions other than phagocytosis did not appear significantly different between the groups. The most common adverse event associated with GM-CSF was fever.

Conclusions GM-CSF did not improve mean neutrophil phagocytosis at day 2, but was safe and appeared to increase the proportion of patients with adequate phagocytosis. The study suggests proof of principle for a pharmacological effect on neutrophil function in a subset of critically ill patients.

  • gm-csf
  • neutrophil biology
  • bacterial infection

This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/

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Footnotes

  • EMP and AJR contributed equally.

  • Contributors AJS, ACM and DFM designed the trial; EMP, AJR, TPH, M-HR-S, JS, JGM, SW, JDW, JKJ and ERC performed experiments; EMP, AJR, AIR, VCL, SVB and SEW recruited patients; AIR, VCL, SVB and SEW were lead investigators at recruiting sites; TC and TF performed statistical analysis; SAB and JP managed the trial and its sites; EMP, AJR and AJS wrote the manuscript. All authors approved the manuscript.

  • Funding This work was funded by a grant from the Medical Research Council (G1100233), with additional support from the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval National Research Ethics Service (NRES) Committee, Yorkshire and The Humber – Leeds West (12/YH/0083).

  • Provenance and peer review Not commissioned; externally peer reviewed.

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